Biomedical subjects

Y I Goto

Publications and source records attributed to Y I Goto.

6 recordsLinked to original sources

PubMed2001

Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA.

Here we investigated the pathogenesis of deletion mutant mitochondrial (mt)DNA by generating mice with mutant mtDNA carrying a 4696-basepair deletion (DeltamtDNA4696), and by using cytochrome c oxidase (COX) electron micrographs to identify COX activity at the individual mitochondrial level. All mitochondria in tissues with DeltamtDNA4696 showed normal COX activity until DeltamtDNA4696 accumulated predominantly; this prevented mice from expressing disease phenotypes. Moreover, we did not observe coexistence of COX-positive and -negative mitochondria within single cells. These results indicate the occurrence of inter-mitochondrial complementation through exchange of genetic contents between exogenously introduced mitochondria with DeltamtDNA4696 and host mitochondria with normal mtDNA. This complementation shows a mitochondria-specific mechanism for avoiding expression of deletion-mutant mtDNA, and opens the possibility of a gene therapy in which mitochondria possessing full-length DNA are introduced.

Animals↗

PubMed2000

Muscle mitochondrial changes by experimental immobility and hindlimb suspension.

It is one of the key themata to investigate the circulatory, muscular, nervous and nutritional systems when humans stay for long time in the space environment in order to improve the safety and efficiency in manned space flight. It is well known that immobility and microgravity [correction of microgravidity] induce selective skeletal muscle atrophy. Previous experiments indicated red soleus muscle was selectively involved and the most striking finding was myofibrillar degeneration without necrosis or phagocytosis. This study is focused on the mitochondrial function in this degenerative process because red soleus muscle contains much mitochondria than white muscles, and mitochondrial changes may be closely associated with the core structure observed as the myofibrillar disorganization.

Animals↗

PubMed1998

Glycogen storage disease type II: identification of four novel missense mutations (D645N, G648S, R672W, R672Q) and two insertions/deletions in the acid alpha-glucosidase locus of patients of differing phenotype.

Glycogen storage disease type II (GSDII), an autosomal recessive myopathic disorder, results from deficiency of lysosomal acid alpha-glucosidase. We searched for mutations in an evolutionarily conserved region in 54 patients of differing phenotype. Four novel mutations (D645N, G448S, R672W, and R672Q) and a previously described mutation (C647W) were identified in five patients and their deleterious effect on enzyme expression demonstrated in vitro. Two novel frame-shifting insertions/deletions (delta nt766-785/insC and +insG@nt2243) were identified in two patients with exon 14 mutations. The remaining three patients were either homozygous for their mutations (D645N/D645 and C647W/C647W) or carried a previously described leaky splice site mutation (IVS1-13T-->G). For all patients "in vivo" enzyme activity was consistent with clinical phenotype. Agreement of genotype with phenotype and in vitro versus in vivo enzyme was seen in three patients (two infantile patients carrying C647W/C647W and D645N/+insG@nt2243 and an adult patient heteroallelic for G648S/IVS1-13T-->G). Relative discordance was found in a juvenile patient homozygous for the non-expressing R672Q and an adult patient heterozygous for the minimally expressing R672W and delta nt766-785/+insC. Possible explanations include differences in in vitro assays vs in vivo enzyme activity, tissue specific expression with diminished enzyme expression/stability in fibroblasts vs muscle, somatic mosaicism, and modifying genes.

Adult↗

PubMed1998

Mitochondrial abnormalities in selenium-deficient myopathy.

We report a man who developed selenium-deficient myopathy during long-term parenteral nutrition. Muscle biopsy showed marked mitochondrial depletion in the deep sarcoplasm and enlarged mitochondria at the periphery mainly in type 2 fibers. Muscle weakness improved gradually after the second course of selenium supplementation. The peculiar mitochondrial abnormalities in muscle fibers appear to play a key role in the pathogenesis of selenium-deficient myopathy.

Adult↗

PubMed1997

New autosomal-recessive syndrome of Leber congenital amaurosis, short stature, growth hormone insufficiency, mental retardation, hepatic dysfunction, and metabolic acidosis.

We report on a new autosomal-recessive syndrome in 4 Japanese children in 2 families. The key manifestations are Leber congenital amaurosis, short stature, growth hormone insufficiency, mental retardation, hepatic dysfunction, metabolic acidosis, and autosomal-recessive inheritance. There were no consanguineous marriages. Abnormal eye movements were noticed neonatally, and ophthalmological examinations showed no visual acuity, pigmentary retinal degeneration, and nonrecordable electroretinograms in all cases. Inadequate weight gain and short stature gradually became apparent after birth, and at present the height range is -4.6 - -7.2 SD (standard deviations). Developmental delay was noted at age 4 months, and the developmental quotient is 50-70 at present. Deterioration of development and convulsions were not recognized. Elevated serum aminotransferase levels and metabolic acidosis were also found at age 4 months. Proximal renal tubular acidosis was clarified by bicarbonate tolerance tests in 1 case, and may have caused metabolic acidosis. Growth hormone secretion was insufficient by insulin tolerance test in 3 cases. One year of growth hormone therapy in 2 cases did not affect growth velocity. Hepatic dysfunction and metabolic acidosis ameliorated later. No renal cysts were found. A cranial computed tomographic scan and magnetic resonance imaging showed normal findings. Amino acids, organic acids, and very long chain fatty acid levels in plasma were all normal in the 3 cases examined. Histopathological and mitochondrial DNA analyses showed no evidence of mitochondrial disorders.

Acidosis↗

PubMed1997

Myoclonus epilepsy associated with ragged-red fibers: a G-to-A mutation at nucleotide pair 8363 in mitochondrial tRNA(Lys) in two families.

In addition to well-known mutations at nucleotide pair 8344 and 8356 in mitochondrial DNA in patients with myoclonus epilepsy associated with ragged-red fibers (MERRF), we found a new G-to-A point mutation at nucleotide 8363 in two Japanese families. The probands had the typical clinical characteristics of MERRF. Since the 8363 mutation was present in a heteroplasmic state, and seen in none of 92 patients with other mitochondrial diseases or 50 normal individuals, this mutation is thought to be disease-related and probably specific to MERRF. As seen in muscle biopsies with the previous two mutations, focal cytochrome c oxidase (CCO) deficiency was the most characteristic finding. With single fiber analysis, the CCO-negative fibers contained a higher percentage of mutant DNA (88.4 +/- 6.6%) than CCO-positive fibers (65.1 +/- 8.0%). These findings suggest that mutations in tRNA(Lys) coding region are related to the MERRF phenotype and are responsible for the reduced CCO activity.

Adolescent↗